Sulphonamides compositions and method for treating edema

ABSTRACT

Pharmaceutical compositions are produced which comprise a compound of the formula:   WHEREIN: R is hydrogen or methyl; R&#39;&#39; is hydrogen or lower alkyl; R&#39;&#39;&#39;&#39; is hydrogen or lower alkyl; and N IS 0 OR 1; OR A PHARMACEUTICALLY ACCEPTABLE NON-TOXIC SALT THEREOF, IN COMBINATION WITH A PHARMACEUTICALLY ACCEPTABLE INERT DILUENT OR CARRIER. These compositions are useful for their saluretic effect and are useful in treating edema and hypertension.   D R A W I N G

ilnite States Patent 1191 Horstmann et al.

1 51 Feb, 4, 1975 SULPHONAMIDES COMPOSITIONS AND, METHOD FOR TREATING EDEMA [76] Inventors: Harald Horstmann,

Wuppertal-Vohwinkel; Hartmund Wollweber; Karl Meng, both of Wup Pertal-Elberfeld, all of Germany [22] Filed: Aug. 10, 1970 [21] Appl. No: 62,639

Related [7.5. Application Data [62] Division of Ser. No. 829,123, May 29, 1969, Pat. No. 3,629,442, which is a division of Ser. No. 643,822, June 6, 1967, Pat. No. 3,499,000.

US. Cl 424/319, 424/279, 424/283 Int. Cl A6lk 27/00 Field of Search .f. 424/283, 279, 319

[56] References Cited UNlTED STATES PATENTS 3,l62,65l l2/l964 Tuckeretal. ..'.424/283 Primary Examiner-Albert T. Meyers Assistant Examiner-Daren M. Stephens Attorney, Agent, or FirmJacobs & Jacobs [57] ABSTRACT Pharmaceutical compositions are produced which comprise a compound of the formula:

6 Claims, No Drawings SULPHONAMIDES COMPOSITIONS AND METHOD FOR TREATING EDEMA This is a divisional of our copending application Ser. No. 829,123 filed May 29, 1969, now US. Pat. No. 3,629,442, which itself is a divisional of our application; Ser. No. 643,822 filed June 6, 1967 now US. Pat. No. 3,499,005.

The present invention is concerned with disulphonamides of the formula:

(III) wherein R is hydrogen or methyl, R is hydrogen or lower alkyl, R" is hydrogen or lower alkyl and n or 1, and their pharmaceutically acceptable non-toxic salts. These compounds have been found to be useful saluretics and have been found to possess a much greater diuretic-saluretic effect than known compounds and a much more advantageous Na /K quotient. 2.4-disulphamyhchlorobenzenes of the formula:

IlzNOgS SOzNII:

are known to have salt-eliminating effects [cf. Jakob, Dtsch.Med. Wschr. 85, 814 (1960)]. It is also known in the art that certain derivatives of 2,4-disulphamylchlorobenzene, in which the sulphamyl radical in the p-position to the chlorine atom is mono-or disubstituted, are superior to the unsubstituted compound in salt-eliminating or saluretic effects (cf. Belgian Pat. No. 598,722; German Pat. Nos. 1,096,897 and 1,111,618).

On comparison with the effectiveness of commercial diuretics of the sulphonamide series, such as hydrochlorothiazide [U.S. Pat, No. 2,809,194; Experientia 14, 458 (1958)], the effect of the benzene-mdisulphonamides referred to abovemust be regarded as poor, and, according to the present state of the art, have only limited clinical interest inapplicability.

All of the above compounds have in common the fact that besides the desired elimination of Na and Cl ions, K ions are simultaneously eliminated to a greater or lesser degree. This results in a very serious contraindication particularly in cases of prolonged therapeutic or clinical application, namely hypopotassemia. It is therefore particularly important for any saluretic which is intended to be administered over anysubstantial period of time that the Na /K* quotient should be as high as possible.

It has been found that disulphonamides of the formula:

(III) aminoalkyl-hydroxy-carboxylic acid ester or salt of the wherein R is hydrogen or methyl, R is hydrogen or lower alkyl, R is hydrogen or lower alkyl and .n is 0 or 1, have a much greater diuretic-saluretic effect and a much more advantageous Na/K quotient than presently known diurctic-saluretic compounds. The disulphonamides (111) may be obtained by a. reacting 4-chloro-3-sulphonamido-benzene sulphochloride of the formula:

ll-.-NO2S- SO-zCl with amines and/or their salts of the formula:

either in the presence or absence of acid-binding agents;

b. by reacting 4-chloro-3-sulphonamido-benzene sulphochloride of the formula:

with an aminoalkyl-hydroxy-carboxylic acid,

formula:

(CHO!) R R HYNCH2\ OY with oxidizing agents; or v d. converting the salts of hydroxycarboxylic acids of the formula:

Qlu

t or I H R R 112N028 -soQ 1 I-crn 000E (VII) in an alkaline medium into the cyclic form ([11) by,acidification. such as with hydrochloric acid, and. if desired, by heating, wherein R is hydrogen or methyl. R is hydrogen or lower alkyl. R is hydrogen or lower alkyl, X is an OH group or its reactive esters. such as the tosyloxy group or halogen. Y is an OH group, O-lower rium in aqueous media according to the following:

(cm)n (cm)n It is also possible to replace the aminoalkyl-hydroxycarboxylic acids (IV) with their-functional derivatives of theformula V, according to process b), such as their hydroxy esters, carboxylic acid salts or carboxylic acid esters. As described in process b), the lactone ring can be closed after the reaction of compounds (V) and (l) by subsequent treatment with hydrolyzing agents, if desired after acidification and heating:

(CH2) n RII R a o OY IIN CPL The disulphonamides (lll) ofthe present application may be present in the form of racemates or in the form of their dextrorotatory or levo-rotatory optically active isomers. Examples 2 and 3 illustrate the production of levo-rotatory and dextrorotatory disulphonamides according to process c).

The oxidizing agents'with which compounds (Vl) are treated include, inter alia, potassium permanganate,-

chromic acid, nitric acid, ruthenium dioxide, manganese dioxide, oxygen or air, at an elevated temperature and increased pressure in the presence of known catalysts.

The disulphonamides of the formula III obtained according to the processes disclosed herein may be present in equilibrium with hydroxycarboxylic acid (Vl l) from which they are derived:

or R 1 HzNOg s -s Og-N-CH: OH

7 (v11 V V In an alkaline medium, the salts of hydroxycarboxylic acids (Vll) may be present to a considerable extent. These compounds are converted into the cyclic form of the disulphonamides (Ill) by acidification, such as with hydrochloric acid, and, if desired, by heating.

With non-toxic bases, disulphonamides (lll) form salts which are derived either from (ill) or (V) depending upon whether one or two equivalents of a corresponding base have been used.

On comparison with known diuretics and saluretics, the compounds of the present invention not only exhibit a higher activity and a substantially improved tin.

Na/K quotient, but they are also suitable for parenteral administration to humans and animals by virtue of the fact that, in contrast to many diuretics-saluretics, they are soluble in the form of their monosalts at an almost neutral pH. No stabilizers are required for the preparation of the aqueous solution to be used for parenteral administration.

The products according to the present invention are also useful for sweeping out edema of various genuses as well as for the treatment of hypertension. In the treatment of edema, preparations containing the disulphonamides of the present invention are administered in a dosage in the range of from 20 to l00 mg per day. When used in the treatment of hypertension, which normally requires treatment for a prolonged period of time, a dosage in the range of 10 to 30 mg per day is used.

The compounds of the present invention may be mixed with pharmaceutically inert carriers, such as talc, lactose, starch, ethylcellulose, agarpectin, stearic acid, magnesiumstearate, sodiumbicarbonate or gela- For parenteral application salts with non-toxic bases of the open ring hydroxycarboxylic acid are used.

These salts enable the preparation of stable aqueous solutions at a substantially neutral pH,

The above-mentioned solid and liquid preparations can be formed into'capsules, tablets, pills,. powder, granulates, suppositories, ampules or drops.

The'following non-limitativ e examples illustrate the production of typical compounds and administration forms of the present invention:

EXAMPLE 1 I90 grams (0.5 mole) chlorobenzene-2,4- disulphonic acid amide-(2)-[a-(a-methyl)- tetrahydrofurfuryl]-N-methylamide-(4) are dissolved in a solution of 40 g NaOH'(l mole) in l litre of water. 126 grams potassium permanganate are added, the mixture is stirred at 50C for 10 hours, filtered off from pyrolusite, thefiltrateis buffered with an ammonium chloride solution and the starting material filtered off. After subsequent acidification with dilute hydrochloric acid, chlorobenzene-2,4-disulphonic acid amide-(2)- [o -(a-methyl-a-oxo)-tetrahydrofurfuryl]-N- methylamide-(4) is precipitated and crystallizes completely in the course of several hours. M.p. 153 to 156C (alcohol), yield 118 g. A further 15 g of crude lactone can be isolated from the mother liquor. The total yield, referred to the reacted starting material, amounts to 81%.

EXAMPLE- 2 Levo-rotatory chlorobenzene-2,4-disulphonic acid amide(2)-[a-(a-methyl-a-oxo),-tetrahydrofurfuryl]- N-methylamide-(4): I

According to the method described in Example l, 19

, g levo-rotatory chlorobenzene-2,4-disulphonic acid (2.0% in methanol) are dissolved in ml of water (dl)-2-methyl-a-aminomethyl-tetrahydrofuran is resolved with (d) (-)-tartaric acid into dextro-rotatory a-methyl-a-aminomethyl-tetrahydrofuran, b.p. 74 to 78C/50 mm Hg, {t1];; +6.65(2.6% in chloroform); hydrochloride mp. 196C, [all- -11.33 (1.5% in methanol), and this is reacted with 4-chloro-3- sulphonamido-benzene sulphochloride to give the levorotatory ch1orobenzene-2,4-disulphonic acid amide- (2)-[a-(a-methyl)-tetrahydrofurfuryll-N- methylamide-(4).

EXAMPLE 3 Dextro-rotatory chlorobenzene-2,4-disulphonic acid amide(2)-[a-(a-methy1-a-oxo)-tetrahydrofurfury1]- N-methylamide-(4):

The product which is obtained in analogy with Example 2 in a yield of 82% by oxidation of 19 g of dextrorotatory chlorobenzene-2,4-disulphonic acid amide- (2)-[a-(a-methyl)-tetrahydrofurfuryl]-N- methylamide-(4) with 12.5 g potassium permanganate in 100 ml of water and 4 g NaOH, has the following constants:

M.p. 168 to 170C, rotation values, measured in methanol c 2.012: 1011 +5.0; [01 +5.7"; l' lmrs HO-7; im-1 l laas Starting material: levo-rotatory a-methyl-a-methylaminomethyl-tetrahydrofuran, b.p. 70 to'74C/45 mm Hg, [M 6.75 (1.6% in chloroform); hydrochloride mp. 196C, [011 +10.9(2.06% in methanol); dextro-rota-tory chlorobenzene-2,4-disulphonic acid amide-(2Mafia-methyl)-tetrahydrofurfuryll-N- methylamide-(4), m.p. 145 to 146C, {ah +17.55 (2.02% in methanol).

EXAMPLE 4 To a solution of'y-hydroxy-y-aminomethyl-valerianic acid ethyl ester acetate, which was obtainedby-hydrogenating 34.2 g y-hydroxy-ycyano-valerianic acid methyl ester in glacial acetic acid with a Pt-catalyst, in 40 ml acetone and 40 ml of water there is simultaneously added dropwise at 20C with vigorous centrifuging a solution of 42.75 g 4-chloro-3-sulphonamidobenzene sulphochloride in 100 ml acetone and a solu-' tion of 31.5 g sodium carbonate in 50 m1 of water. The mixture is stirred overnight, filtered off from inorganic components, concentrated by evaporation in a vacuum, the residue is taken up with water/dilute hydrochloric acid and the organic components are extracted with a mixture ofether/ethyl acetate. After evaporation of the organic phase there remain 10g of an oil which completely crystallizes after brief heating with dilute hydrochloric acid to give chlorobenzene-2,4- disulphonic acid amide-(2)-[a-(a-methyl-oU-oxo): tetrahydrofurfuryl]-amide-(4), m.p. 188, to 189.5C (alcohol/water).

EXAMPLE 5 According to the method described in Example 4 it is also possible to start from a-aminomethyl'a-methyh butyrolactone acetate which is obtained by catalytic hydrogenation of wcyano-a-methyhbutyrolactone in glacial acetic acid by means of a Pt-catalyst, and to react this with 4-chloro-3-sulphonamido-benzene sulphochloride in acetone in the presence ofa sodium carbonate solution. After appropriate working up there is obtained chlorobenzene-Z.4-disulphonic acid amide- 6 (2)-[a-(a-methyl-oz-oxo)-tetrahydrofurfuryl]-amide- (4), mp. 188 to 189.5C.

' EXAMPLE 6 A solution of y-hydroxy-y-methy]aminomethylvalerianic acid-lactone hydrochloride is reacted according to the method described in Example 2, with 4- chloro-3-sulphonamido-benzene sulphochloride in acetone in the presence of water. After appropriate working up, there is obtained chlorobenzene'2,4- disulphonic acid amide-(2)-[u-(a-methyl-a'-oxo)- tetrahydrofurfuryl]-N-methylamide-(4) ofm.p. 153 to 156C in a yield of 22%. v

The y-hydroxy-y-methylaminomethyl-valerianic acid-lactone hydrochloride is obtained in the following manner:

2/10 mole y-hydroxy-y-cyano-valerianic acid methyl ester are hydrogenated in glacial acetic acid with a Ptcatalyst. The mixture is evaporated in a vacuum, and residue dissolved in a little alcohol, 26.5 g benzaldehyde are added and then 6.5 g NaQH dissolved in ml of alcohol are slowly added dropwise at 20C. After the addition of benzene, the mixture is stirred at 50C for 10 minutes, evaporated in a vacuum, taken up with 200 ml of benzene and, after the addition of 22 g dimethyl sulphate, heated at 90C for a good 20 minutes. The reaction product is decomposed with dilute hydrochloric acid, the precipitated benzaldehyde is extracted with ether and after evaporation there is obtained crude yhydroxy-y-methylamino-methyl-valerianic acid-lactone hydrochloride which is reacted, without previous purification, with 42 g 4-chloro3- sulphonamido-benzene sulphochloride.

EXAMPLE 7 In analogy with Example 1, there were obtained: Chlorobenzene-2,4-disulphonic acid amide-(2)-[a- (a-oxo-tetrahydrofurfuryll-N-methylamide-(4) of the l s so -n-cn m.p. 142 145C., yield 38% of theory.

EXAMPLE 8 50 g of chlorobenzene-2,4-disulphonic acid amide- (2-[ a-( a-methyl-a-oxo )-tetrahydrofurfuryl ]-N- methylamide-(4), 7 g of sodiumbicarbonate and 2.5 g of magnesium stearate are ground and filled with gelatin capsules each containing 0.05 g.

IIzNOzS H NO amide-(2)- EXAMPLE 9 396.5 g of chlorobenzene-2,4-disulphonic acid amide-( 2 a-( a-methyl-a-oxo)-tetrahydrofurfuryl N-methylamide-(4) is dissolved in 2000 ml of l n NaOH solution. The solution is heated for l hour to 100C, cooled and the pH is adjusted to 7.2 by the addition of l n HCl (about 950 ml 1 n HCl) and filled up to 10 litres by adding distilled water. The solution is sterilized and filled into ampules of l or 2 ml.

What is claimed is:

l. A pharmaceutical composition useful in a human or animal to eliminate excess or undesired salt from the body fluids, in the treatment of edema'and in the treatment of hypertension which consists of an effective amount of a compound of the formula:

R is hydrogen or methyl;

R is hydrogen or lower alkyl;

R is hydrogen or lower alkyl; and

n is or 1; or a pharmaceutically acceptable non-toxic salt thereof, in combination with a'pharmaceutically acceptable inert diluent or carrier.

2. A method of eliminating excess or undesired salt from the body fluids ofa human or animal which comprises administering to a human or animal in need thereof an amount of a compound of the formula:

a pharmaceutically acceptable non-toxic salt thereof or a compound of the'formula,

animal from 20 mg to 100 mg per day .of a compound of the formula:

a pharmaceutically acceptable non-toxic salt thereof,

R is hydrogen or methyl;

R is hydrogen or lower alkyl;

R" is hydrogen or lower alkyl; and

n is 0 or 1; or a pharmaceutically acceptable non-toxic salt thereof, sufficient to be effective in the treatment of edema in humans and animals.

5. A method of treating hypertension in humans and animals which comprises administering to such human 'or animal an antihypertensive amount of a compoun of the formula Y wherein:

R is hydrogen or methyl; R is hydrogen or lower alkyl; R is hydrogen or lower alkyl; and n is '0 or I; or a pharmaceutically acceptable non-toxic salt thereof. a

6. A method according to claim 3 wherein the amount administered isfrom 10 to 30 mgs per day 

1. A PHARMACEUTICAL COMPOSITION USEFUL IN A HUMAN OR ANIMAL TO ELIMINATE EXCESS OR UNDESIRED SALT FROM THE BODY FLUIDS, IN THE TREATMENT OF EDEMA AND IN THE TREATMENT OF HYPERTENSION WHICH CONSISTS OF AN EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA:
 2. A method of eliminating excess or undesired salt from the body fluids of a human or animal which comprises administering to a human or animal in need thereof an amount of a compound of the formula:
 3. A method of treating edema in humans and animals which comprises administering to such human or animal from 20 mg to 100 mg per day of a compound of the formula:
 4. A method of treating edema in humans and animals which comprises administering to such human or animal an amount of a compound of the formula:
 5. A methOd of treating hypertension in humans and animals which comprises administering to such human or animal an antihypertensive amount of a compound of the formula
 6. A method according to claim 3 wherein the amount administered is from 10 to 30 mgs per day. 